Urologia 2013 ; 80 ( 4 ): 265- 275

DOI: 10.5301/urologia.5000041

REVIEW

Urinary markers in the everyday diagnosis of bladder cancer Fabrizio Dal Moro, Claudio Valotto, Andrea Guttilla, Filiberto Zattoni Department of Surgical, Oncological and Gastroenterological Sciences, Urology Clinic, University of Padova, Padova - Italy

Bladder cancer (BC) represents the fourth most common neoplasia in men and the ninth most common cancer in women, with a significant morbidity and mortality. Cystoscopy and voided urine cytology (involving the examination of cells in voided urine to detect the presence of cancerous cells) are currently the routine initial investigations in patients with hematuria or other symptoms suggestive of BC. Around 75-85% of the patients are diagnosed as having non-muscle-invasive bladder cancer (NMIBC). Despite the treatment, these patients have a probability of recurrence at 5 years ranging from 50 to 70% and of progression to muscle invasive disease of 10-15%. Patients with NMIBC must undergo life-long surveillance, consisting of serial cystoscopies, possibly urine cytology and ultrasonography. Cystoscopy is unsuitable for screening because of its invasiveness and costs; serial cystoscopies may cause discomfort and distress to patients. Furthermore, cystoscopy may be inconclusive, falsely positive or negative. Although urine cytology has a reasonable sensitivity for the detection of high-grade BC, it lacks sensitivity to detect low-grade tumors (sensitivity ranging from 4 to 31%). The overall sensitivity and specificity of urine cytology range from 7 to 100 and from 30 to 70%, respectively. There is a need for new urine biomarkers that may help in BC diagnosis and surveillance. A lot of urinary biomarkers with high sensitivity and/or specificity have been investigated. Although none of these markers have proven to be powerful enough to replace standard cystoscopy, some of them may represent accurate predictors of BC. A review of recent studies is presented. Key words: Bladder cancer, Urinary markers, Cystoscopy, FISH, Genomics, Proteomics Parole chiave: Tumore vescicale, Markers urinari, Cistoscopia, FISH, Genomica, Proteomica Accepted: September 30, 2013

INTRODUCTION Bladder cancer (BC) represents the fourth most common neoplasia in men and the ninth most common cancer in women, with a significant morbidity and mortality (1). Cystoscopy and voided urine cytology (involving the examination of cells in voided urine to detect the presence of cancerous cells) are currently the routine initial investigations in patients with hematuria or other symptoms suggestive of BC. Around 75-85% of the patients are diagnosed as having non-muscle-invasive bladder cancer (NMIBC), confined to the epithelium or subepithelial connective

tissue. These cancers are usually managed with a rigid white light cystoscopy under regional or general anesthesia and by means of transurethral resection of the BC. Despite the treatment, these patients have a probability of recurrence at 5 years ranging from 50 to 70% and of progression to muscle invasive disease of 10-15% (2, 3). As the risk of local recurrence extends over the lifetime, patients with NMIBC must undergo life-long surveillance, consisting of serial cystoscopies, eventually urine cytology and ultrasonography. Although cystoscopy is the mainstay in BC diagnostic process, the procedure is unsuitable for screening because of

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its invasiveness and costs; in addition, serial cystoscopies may cause discomfort and distress to patients. Furthermore, cystoscopy may be inconclusive, falsely positive or negative, due to clinician’s mistake or because of the presence of small areas of tumor or carcinoma in situ (CIS) that may be difficult to be recognized (4). Additionally, although urine cytology has a reasonable sensitivity for the detection of high-grade BC, it lacks sensitivity to detect low-grade tumors (sensitivity ranging from 4 to 31%) (5). The overall sensitivity and specificity of urine cytology range from 7 to 100 and from 30 to 70%, respectively (6-46). For the above-mentioned reasons, there is a need for new urine biomarkers that may help in BC diagnosis and surveillance (47-48). An ideal BC marker would allow us to accurately monitor patients with a history of BC, identify early recurrence and prevent disease progression. It should be non-invasive, objective, accurate, rapid and easy to administer and interpret, with high sensitivity and specificity. Because of the relatively low prevalence of BC in the general population, BC screening would probably not be costeffective, although potentially feasible if a very low cost marker becomes available (49). A lot of urinary biomarkers with high sensitivity and/or specificity have been investigated. Although none of these markers have proven to be powerful enough to replace standard cystoscopy, some of them may represent accurate predictors of BC. Despite this evidence, these new tests have not been implemented as an adjunct to existing surveillance and detection protocols. A review of recent studies is herein presented regarding the most important and emerging BC markers.

MATERIALS AND METHODS

FLURESCENCE IN SITU HYBRIDIZATION (FISH) FISH is a molecular test that uses DNA probes to identify the most common urothelial BC-related chromosomal changes in urine exfoliated cells. Urovysion (Abbott Molecular, Inc., Des Plaines, IL) is a multitarget assay that detects aneuploidy in chromosomes 3, 7 and 17 as well as loss of the 9p21 locus of the P16 tumor suppressor gene. In various studies (9, 18, 24, 29-30, 33, 50-62), the sensitivity of FISH varied between 64 and 96%. All Authors reported a low sensitivity of FISH to detect low-grade (36-57%) and low-stage (62-65%) tumors, while FISH demonstrated a high sensitivity to detect high-grade and high-stage tumors (8397%). Similarly, the sensitivity for the detection of CIS was close to 100%. The specificity of FISH is high (73-97%) and is comparable to cytology. The combination of cytology and FISH detects 97.4% of cancers (10). Kipp demonstrated that FISH might be used to monitor the effects of BCG and other intravesical therapies: patients with a positive FISH test assay have been shown to develop recurrence earlier and are 9.4 times as likely for progression to muscle-invasive tumor as those with a negative post-therapy FISH (63). Disadvantages of this test are represented by the high costs of the probes and the need for expensive equipment (fluorescent microscopy, specific filters, trained technical personnel) (54).

BLADDER TUMOR ANTIGEN (BTA)

A systematic literature search using Medline/PubMed database for full-length papers was performed up to August 31, 2012. Entry terms were bladder cancer OR urinary markers OR genomics OR proteomics OR hybridization OR cystoscopy. Two authors (FDM and AG) reviewed the abstracts of the retrieved records and selected only those pertinent to the objectives of the present review. All authors carefully examined the corresponding full-length articles, and they hand-searched and retrieved additional referenced papers. Only those articles reporting 266

complete data with clinical relevance for the present review (i.e., description of the type of markers, operative technique, and oncological results) were considered for analysis. In the case of two or more papers reporting on the same updated series, only the most recent one was selected. Review articles were also analyzed.

BTA Stat and BTA-TRAK™ are designed to detect BCassociated antigen in voided urine. This antigen has been recognized as a human complement factor H related protein (hCFHrp); it inhibits the complement pathway to cause cytolysis in cells, with a resulting selective advantage for the tumor. BTA interacting with complement factor C3b interrupts the complement cascade, potentially conferring a selective growth advantage to cancer cells. In cell culture, normal cells do not express the H-related protein. BTA Stat

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is an immunochromographic qualitative point-of-care test with an immediate result, whereas BTA-TRAK is a quantitative test that requires well-trained personnel and a reference laboratory. The overall sensitivity and specificity for the BTA stat test are 57-83% and 60-92%, respectively (7-9, 39, 53, 57, 64-68). Sensitivity of the BTA-TRAK varies considerably depending on the cut-off limit. The cut-off value recommended by the manufacturer for the BTA-TRAK test for detecting BC is 14 units/mL (69). In many studies, the sensitivity of the BTA-TRAK is 62-77% and specificity is 50-75% when using this value as the cut-off limit (70-72). Considering different cut-off levels also, the reported sensitivity and specificity ranges are 51-100% and 73-92.5%, respectively (7, 17-18, 53, 67, 73).

NUCLEAR MATRIX PROTEIN 22 (NMP22) Nuclear matrix proteins make up the non-chromatin structure that confers nuclear shape, organizes the chromatin and regulates critical aspects of mitosis. If improper distribution of chromatids occurs with mitosis, there is a 25-fold increase in nuclear mitotic apparatus protein when compared with the concentration in cells from the normal bladder. The nuclear matrix protein 22 (NMP22) test is an enzyme immunoassay for nuclear mitotic apparatus protein (a component of the nuclear matrix) in voided urine: in the urine of patients with BC there is a substantially higher level of NMP22. The normal values of NMP22 are different for men and women, and normal women have higher NMP22 levels in their urine than age-matched men. The median value for a normal woman aged 50 to 70 years is 3.90 versus 2.38 U/mL for men. This difference is statistically significant (74). Nuclear matrix protein 22 is not a perfect bladder tumor marker, and false-positive and false-negative findings can be significant. In fact, because this protein is released from dead and dying urothelial cells, many non-malignant conditions of the urinary tract, such as stones, infection, inflammation, and hematuria, as well as instrumentation (i.e., cystoscopy), can cause a false-positive test result. The sensitivity of the original NMP22 immunoassay has ranged from 33 to 100% and its specificity from 46 to 93% depending on the cut-off value used (8, 11-12, 20-22, 26-27, 34, 36, 38-39, 41-42, 44-46, 57, 70-71, 75-88). Of interest, intravesical bacillus Calmette-Guérin seems to not alter the performance characteristics of NMP22 (89),

although NMP22 nowadays could not be recommended as the preferred marker to follow-up patients treated with BCG. The test is simple to administer. If used as the first-line test in a patient complaining of hematuria, the result would be available in real time for consultation and could therefore be used by the urologist to optimize the choice of further investigations, with the potential for reducing the discomfort and risk of unnecessary flexible cystoscopy as well as financial savings.

IMMUNOCYT The ImmunoCyt/uCyt+ test (Diagnocure™) is an immunocytological fluorescence assay designed to improve the sensitivity of cytology. Three fluorescent-labeled monoclonal antibodies are used to detect antigens originating specifically from tumors of transitional epithelial cells. These antigens are M344, LDQ10 and 19A211. Schmitz-Dräger et al. (90) showed that the combination of cystoscopy and ImmunoCyt testing provided 100% sensitivity in TCC detection, whereas combining cystoscopy and cytology marginally improved upon the sensitivity of cystoscopy alone. Nevertheless, in several studies, the sensitivity of uCyt varies between 38% and 100%, and the specificity ranges between 62% and 90% (18, 28, 31-33, 35, 40, 43, 91-94). Reasons for the wide range of differences in sensitivity among various studies may be manifold and are largely owing to patient selection. However, immunocytology is an observer-dependent technique that requires broad personal experience and constant quality control.

LEWIS X The Lewis X is a blood group antigen that is normally absent from urothelial cells in the adult, but is expressed in transitional cell tumors regardless of the secretor status, grade, or stage of the tumor. The ranges of sensibility and specificity of this test in different published studies are from 79.8 to 85% and from 80 to 86.4%, respectively (95-97). Studies of bladder barbotage specimens have demonstrated an overall sensitivity of 85% compared to only 61% of urine cytology (98). By combining both methods, the sensitivity increases to 93%. Interestingly, Lewis X immunocytology is independent of tumor grade/stage and particularly sensitive for detecting low-grade carcinomas (97). In addition, the test

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seems to be useful for predicting tumor recurrence and/or progression (99).

TELOMERASE Telomeres are the segments at the ends of eukaryotic chromosomes that provide stability. They consist of tandem “TTAGGG” repeats at the ends of chromosomes, and they become shortened progressively after each cellular division. After multiple divisions, the cell loses telomeres and damage to parent DNA occurs. Subsequent chromosomal instability finally leads to cell death. Telomorase is a ribonucleoprotein that is known to re-extend telomeres to their original length by synthesizing tandem repeats of TTAGGG to the ends of chromosomes and escaping cellular senescence in, for example, germ cells, hemopoietic stem cells, and tumor cells (99-100). Telomerase activity is measured by TRAP, which involves PCR amplification of in vitro telomerase reaction products. The overall sensitivity of urine-based TRAP assays for the detection of BC is mostly between 70 and 90%, although much lower sensitivity was reported in some studies; the specificity of the telomerase assay (i.e., both TRAP and hTERT RT-PCR) in various studies ranges between 43.8% and 93.5% (38, 67, 75, 100-109). However, when patients with inflammatory conditions or benign urologic disease are included as healthy controls, specificity may be lower because of the contaminating benign cells with telomerase activity (i.e., lymphocytes).

HYALURONIC ACID Hyaluronic Acid (HA) is an extracellular glycosaminoglycan that is known to regulate tumor cell adhesion, proliferation, migration, and angiogenesis, and offers some protection from immune system surveillance in tumor tissues. It is a component of tissue matrix and fluids. Concentration of HA is elevated in certain human cancers such as colon, breast, etc. (110-111). Lokeshwar et al. (112) found that hyaluronic acid was increased in the urine of patients with BC (sensitivity of 83.1%, specificity of 90.1%) and was more sensitive in detecting low-grade tumors compared to high-grade tumors. Other studies demonstrated sensitivity ranging from 61 to 83% and specificity from 53.6 to 90.1% (113-114). 268

Small fragments of HA stimulate angiogenesis and are produced by hyaluronidase (HAase) (115). HAase showed a sensitivity of 81.5% and a specificity of 83.8% for highergrade tumors. Hyaluronoglucosaminidase-1 (HYAL-1) is a specific HAase that has been identified as a marker for cancer detection, and is a molecular predictor for tumor growth, invasion, and angiogenesis. At a cut-off value of 100 ng/mL, urine hyaluronic acid has been shown to yield 92% sensitivity and 93% specificity for detecting BC (112). The 2-test combination of HA and HAase demonstrated sensitivity of 91.2% and specificity of 84.4% (116).

BLCA-4 AND BLCA-1 BLCA-4 and BLCA-1 are nuclear transcription factors present in BC. Overexpression of BLCA-4 seems to increase the growth rate in cells. BLCA-4 is analyzed with ELISA and has reported sensitivity between 89% and 96.4%, and specificity between 95% and 100% (117-122). BLCA-1, another nuclear matrix protein expressed in BC, showed sensitivity of 80% and specificity of 87% (121).

PROTEOMICS AND GENOMICS Recent proteomic technologies have offered a promising opportunity for the identification of new BC biomarkers. The key, but little understood, technology in mass spectrometrybased proteomics is peptide sequencing. Two-dimensional gel electrophoresis is conventionally used as a first step to separate and isolate the proteins. Gel electrophoresis techniques are suited for combining with technologies such as laser capture microdissection and highly sensitive mass spectrometry. Additionally, surface-enhanced laser desorption/ionization time-of-flight analysis enables the high-throughput characterization of lysates from urine and may be best suited not only for diagnosis, but also for monitoring BC. Using these techniques, Chemokine CXCL-1 and Matrix Metalloproteinase NMP-22 and NMP-9 have been identified (123). The ADAM28 has been identified as possible biomarker of BC (124). Recent studies have shown a potential role as BC markers of γ-Synuclein and a soluble isoform of Catechol-o-methyltransferase: a concomitant examination of these markers demonstrated an overall sensitivity and specificity of 76.8% and 77.4%, respectively (125).

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Genomics is the study of DNA or RNA sequence and gene expression differences resulting in signature expression for various cancer types. Aurora Kinase A (AUKA) is localized at the centrosome from the time of centrosome duplication to mitotic exit and regulates centrosome function (126). The AUKA gene encodes a serine/threonine kinase associated with aneuploidy and chromosome instability. AUKA has been explored in urine demonstrating a sensitivity of 87% and a specificity of 97% to detect BC (127).

MICROSATELLITE ANALYSIS In patients with BC one of the most common genetic changes is loss of heterogeneity in chromosome 9 (128), but chromosomes 4p, 8p, 9p, 11p, and 17p also often display loss of heterogeneity (129-130). This loss of heterogeneity can be used as a biomarker of neoplastic processes. Several studies have analyzed voided urine with microsatellite biomarkers: the overall sensitivity from these studies ranged from 72 to 97%, and overall specificity ranged from 80 to 100% (128, 131).

OTHER INVESTIGATIONAL MARKERS Many other potential biomarkers have been evaluated for their potential usefulness as urinary tumor markers. Recent studies have evaluated the role of angiogenesis on the tumor growth and progression. In the angiogenesis system, cell adhesion molecules play a role in vascular morphogenesis and endothelial signaling (132). Urinary levels of Human Carcinoembryonic Antigen-related Cell Adhesion Molecule 1 (CEACAM1), a molecule with proangiogenic activity, are significantly higher in patients with BC compared with normal individuals. Tilki et al. have demonstrated a sensitivity of 74% and a specificity of 95% for detecting BC (133). The clinical significance of serum levels of proto-oncogenes has already been evaluated in different human cancers (134). There are pilot studies on the significance of urinary levels of proto-oncogenes as neoplastic markers. Kim et al. have evaluated the role of HER-2 demonstrating that patients with BC have significantly higher urinary levels than normal controls, with a sensitivity and specificity of 71.1 and 84%, respectively (135).

Some of other promising studied markers are Cytokeratin CK20 (136-138), Soluble FAS (139), Survivin (140-142), and UPK3A (143). Larger, multicenter studies are needed to provide more knowledge of the validity of these tests. Pal et al. demonstrated that the urinary level of CA19-9 may be a useful non-invasive test to diagnose the urothelial carcinoma of the bladder (144). Another area of interest is represented by the use of metabonomic profiling to identify a potential specific biomarker pattern in urine as a BC detection strategy. Huang et al. have used Carnitine C9:1 and component I, combined as a biomarker pattern, demonstrating a sensitivity and specificity up to 92.6 and 96.9%, respectively, for BC detection (145).

COMBINATIONS OF TESTS There is a growing consensus that effective and accurate detection of early-stage cancer will likely rely on biomarker panels having greater specificity and sensitivity than each single biomarker, as contributes independent diagnostic information (146). The combined analysis of different markers with different functional molecular targets could improve the general sensitivity and specificity of transitional BC diagnosis in urine. Considering the studies with combination of FISH and Cytology, the reported sensitivity and specificity are 100% and 50%, respectively (147-148). Six studies reported sensitivity and specificity for Immunocyt and cytology used in combination: the mean values are 87% and 68%, respectively (28, 31-33, 35, 43). Two studies reporting a value of 91% of sensitivity for the combination of NMP22 and cytology (26, 149).

CONCLUSION A number of urine-based markers have been identified and evaluated for the diagnosis of BC (Tab. I). The aim of developing urine-based markers in diagnosing BC is to intercept patients with symptoms suggestive of the disease before they undergo invasive cystoscopy (150). Then, high sensitivity (about 100%) is needed so that practically no patients with BC will be missed and preferably high specificity, to prevent patients from unnecessarily undergoing cystoscopy. In addition, tests should be noninvasive, fast and low in cost.

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Table I - Urinary markers sensitivity and speCificity Urinary Marker

Sensitivity Range (%)

Specificity Range (%)

References

Cytology

7-100

78-100

[6-46]

Fish

64-96

73-97

[9, 18, 24, 29-30, 33, 50-62]

BTA Stat

50-83

60-92

[7-9, 39, 53, 57, 64-68]

BTA-TRAK

51-100

73-92.5

NMP22

33-100

46-93

[8, 11-12, 20-22 ,26-27, 34, 36, 38-39, 41-42, 44-46, 57, 70-71, 75-88] [18,28,31-33,35,40,43,91-94]

[7, 17-18, 53, 67, 73]

Immunocyt

38-100

62-90

Lewis X

79.8-85

80-86.4

70-90

43.8-93.5

[38,67,75,100-109]

61-83.1

53.6-90.1

[113-114]

Telomerase Hyaluronic Acid HA

Although many comparative studies have been reported, the hierarchy in diagnostic accuracy of available markers is not yet clear (151). In a recent multivariable analysis (152), cytology was found to have the best specificity and telomerase the best sensitivity. Considering the economic impact of the use of urinary biomarkers, Lotan et al. reported that screening of all men aged 55 years or older was significantly more costly on a per-cancer basis than screening only in a high-risk population (400,000 US$ versus 3,130 US$) (153). A recent paper presented the results of a European screening study in which all patients with negative history for bladder cancer were tested with dipsticks test followed by urinary markers. They demonstrated that a screening protocol substantially reduced the number of cystoscopy recommendations compared with dipstick testing alone and had very few missed cancers. However, a mass screening program was not useful in an unselected asymptomatic European male population (154). Until now, several urine-based markers have been studied, but it seems that none of them is able to replace cystoscopy plus cytology in the diagnosis of lower urinary tract urothelial cancer; it seems that in some types of low-grade bladder cancer they can help safely reduce the use of most

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[95-97]

invasive tests (154). The novel tests have demonstrated the potential for further development as new urinary markers and should be further evaluated to determine their possible clinical utility. Disclaimers Informed consent: The manuscript does not report the results of an experimental investigation on human subjects. Financial support: The authors did not receive any financial support for this study. Conflict of interest: No conflict of interest was identified.

Corresponding Author: Fabrizio Dal Moro Urology Clinic University of Padova Via Giustiniani, 2 35128, Padova, Italy [email protected]

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